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The role of hyperuricemia and gout in kidney and cardiovascular disease

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ASSOCIATION OF HYPERTENSION AND HYPERURICEMIA

The strong association between hypertension and hyperuricemia has been recognized for more than a century. In his original description of essential hypertension in 1879, Frederick A. Mohamed noted that many of his subjects came from gouty families.7 Studies from the 1950s and 1960s showed the prevalence of hyperuricemia in hypertensive subjects to be between 20% and 40%.8,9 The prevalence of hypertension among gouty patients is Hyperuricemia predicts ESRD between 25% and 50%.10 In 1972, Kahn et al found that a rising level of serum urate is an independent risk factor for hypertension.11 A year later, Klein et al demonstrated a linear relationship between serum urate level and systolic blood pressure in both black and white subjects.12

Six large epidemiologic studies published over the past 7 years have found that serum urate level predicts the later development of hypertension.13–18 The most recent of these is the Normative Aging Study,18 which showed that the serum urate level independently predicts the development of hypertension when using age-adjusted and multivariate models that include body mass, abdominal girth, alcohol use, serum lipid levels, plasma glucose level, and smoking status.

A potential mechanism emerges

No clear causal or mechanistic link between elevated serum urate and the development of hypertension was evident until a rat model of mild hyperuricemia was found to be associated with the development of an initial salt-insensitive hypertension that was reversible with restoration of normal urate levels.19 However, if the urate-induced hypertension was allowed to persist, the rat would develop a salt-sensitive hypertension that was irreversible even if normouricemia was reestablished.19

This mechanism was tested in a small pilot study of 5 children with previously untreated essential hypertension who received monotherapy with allopurinol for 1 month.20 All 5 children had substantial drops in their continuously monitored ambulatory blood pressure, and 4 of the 5 developed normal blood pressure (as assessed by continuous monitoring). After the allopurinol was stopped, the blood pressure of all 5 children rebounded to baseline levels.20 A larger blinded, randomized, placebo-controlled crossover trial using the same intervention with similar results has been presented recently at national meetings.21

ASSOCIATION BETWEEN CARDIOVASCULAR DISEASE AND HYPERURICEMIA

There is considerable documentation that urate levels correlate with many recognized cardiovascular risk factors, including age, male gender, hypertension, diabetes mellitus, hypertriglyceridemia, obesity, and insulin resistance. Because of these relationships, the observed association between serum urate elevations and cardiovascular disease was considered to be “epiphenomenal” and not causal. Many older epidemiologic studies that demonstrated the increased cardiovascular risk associated with higher urate levels used traditional statistical techniques that could not prove the “independence” of urate as a risk factor.22

An independent effect is finally documented

Three studies published in the past several years demonstrate an independent risk relationship between hyperuricemia and cardiovascular disease, including acute myocardial infarction.23–25

Multivariate regression analysis of the Multiple Risk Factor Intervention Trial (MRFIT) database demonstrated hyperuricemia to be an independent risk factor for acute myocardial infarction.23

Similarly, the Italian Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA) study showed that after adjustment for age, sex, diabetes, serum lipid levels, serum creatinine, left ventricular hypertrophy, blood pressure, and diuretic use, serum urate levels in the highest quartile were associated with increased risk of all cardiovascular events (relative risk [RR] = 1.73) and fatal cardiovascular events (RR = 1.96) compared with urate levels in the second quartile.24

Finally, follow-up of 4,385 participants in the Rotterdam Study over an average of 8.4 years revealed that high urate levels were a strong predictor of both myocardial infarction and stroke, even after adjustment for other vascular risk factors.25

CONCLUSIONS

Based on the preponderance of recent epidemiologic studies, it appears that an elevated serum urate level is an independent risk factor for kidney disease, hypertension, and cardiovascular disease. The precise mechanisms for urate-induced tissue injury remain unclear, and no large study to date has convincingly demonstrated that lowering serum urate levels can prevent or lessen the risk of these potentially severe complications of hyperuricemia.

It should also be emphasized that the treatment of hyperuricemia with medications such as allopurinol or probenecid is currently not indicated in patients with hypertension, kidney disease, or heart disease. The use of these agents is supported only in the treatment of gout, the treatment of uric acid kidney stones, and the prevention of tumor lysis syndrome.

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